7-benzoyl indolines

ABSTRACT

1,2-Dihydro-7-phenylpyrrolo(3,2,1-jk)(1,4)benzodiazepin-4(5H)ones; 6,7-dihydro-7-phenylpyrrolo(3,2,1-jk)(1,4)benzodiazepin4(5H)-ones; 7-phenylpyrrolo(3,2,1-jk)(1,4)benzodiazepin-4(5H)ones; 1,2-dihydro-6-phenylpyrrolo(1,2,3-ef)(1,5)benzodiazepin4(5H)-ones; 1,2-dihydro-4-phenylpyrrolo(1,2,3-ef)(1,5)benzodiazepin-6(7H)-ones and 1,2,4,5-tetrahydro-4-phenylpyrrolo(1,2,3-ef)(1,5)benzodiazepin-6(7H)-ones, processes for preparing the same and novel intermediates prepared by said processes. The novel compounds of this invention exhibit tranquilizing and anticonvulsant activity in animals.

United States Patent Hester, Jr. 1 July 25, 1972 541 7 -BENZOYLINDOLINES [72] Inventor: Jackson B. Hester, Jr., 6126 Devon, Pri'naryExami' 'er AleX Maze] Portage, Mich 4908] Assistant Examiner-JosephA. Narcavage Attorney-John Kekich et al. [22] Filed: Dec. 4, 1970 [62]Division of Ser. No. 873,718, Nov. 3, 1969, Pat. No.

[52] U.S. Cl ..260/326.l1 [51] lnt.Cl... ....C07d 27/38 [58]Fieldot'Search ..260/326.1l

[56] References Cited UNITED STATES PATENTS 3,314,942 4/1967 Hester..260/239.3

[5 7] ABSTRACT l,2-Dihydro-7-phenylpyrrolo[ 3,2, l -jk][1,4]benzodiazepin- 4(5H)-ones; 6,7-dihydro-7-phenylpyrrolo[ 3,2, l -jkl,4]benzodiazepin-4(5H)-ones; 7-phenylpyrrolo[3,2,1-jk][ l,4]benzodiazepin-4( 5 H)-ones; 1,2-dihydro-6-phenylpyrrolol 1,2,3-ef][1,5 1benzodiazepin-4(5l-l)-ones; l,2dihydro-4- phenylpyrrolo[ l,2,3-ef][l,5]-benzodiazepin-6(7H)-ones and l,2,4,S-tetrahydro-4-phenylpyrrolo-[l,2,3-ef][ l,5]benzodiazepin-6( 7H)-ones, processes for preparing thesame and novel intermediates prepared by said processes. The novelcompounds of this invention exhibit tranquilizing and anticonvulsantactivity in animals.

12 Claims, No Drawings 7-BENZOYL INDOLINES This is a division ofapplication Ser. No. 873,718, filed Nov. 3, 1969, now US. Pat. No.3,579,503.

BRIEF SUMMARY OF THE INVENTION This invention relates to novel1,2-dihydro-7-phenylpyrrolo-[3,2,l-jk][ l,4]benzodiazepin-4(SID-ones (Iand I), 6,7- dihydro-7-phenylpyrrolo[ 3,2, l -jk][ l ,4]benzodiazepin-4(5H)-ones (ll), 7-phenylpyrrolo[3,2,l-jk][1,4 ]benzodiazepin-4(5H)-ones(Ill), 1,2-dihydro-6-phenylpyrrolo[ l ,2,3,-ef][ 1,5]benzodiazepin-4(5H)-ones (IV), 1,2- dihydro-4-phenylpyrrololl,2,3,-ef][ l ,5 ]benzo-diazepin-6 (7l-I)-ones (V) and1,2,4,5-tetrahydro-4-phenylpyrrolo-[l,2,3-ef][l,5]benzodiazepin-6(7H)-ones (VI), processes for preparing thesame and novel intermediates prepared by said processes. The novelcompounds of the invention have the formulas:

wherein R is selected from the group consisting of hydrogen, alkyl offrom one to three carbon atoms, inclusive, alkoxy of from one to threecarbon atoms, inclusive, bromo, chloro and The term "novel compounds"and novel intermediates" of this invention, as used throughout thespecification embraces compounds represented by formulas I, I, ll, III,IV, V and V], the acid addition salts thereof, the compounds of formulasVII and VII and the acid addition salts of VII and VII wherein R, ishydrogen. The term alkyl is inclusive of methyl, ethyl, propyl andisopropyl. The term alkoxy is inclusive of methoxy, ethoxy, propoxy andisopropoxy.

The novel compounds of the invention can be prepared by processesrepresented by the following equations.

VHS.

wherein R is the same as above.

VIIa

fluoro; and R is selected from the group' consisting of hydrogen, alkylof from one to three carbon atoms, inclusive, and alkoxy of from one tothree carbon atoms, inclusive.

The novel intermediates of this invention have the formulas:

VII

VII

wherein R is the same as above and R, is selected from the groupconsisting of hydrogen, acetyl and bromoacetyl.

VII 5 wherein R is the same as above.

Pd/C I I decalin \N wherein R isthe same as above.

vwherein R is the same as above.

DETAILED DESCRIPTION Processes A and B can be utilized to preparecompounds of formulas I and I.v I

PROCESS A In step I, the 7-benzoylindoline (VIIa or VII'a) and'bromoacetyl bromide in benzene is refluxed gently for 1-5 hours toyield a l-(bromoacetyl)-7-benzoylindoline (VIII; or Vll'b). Othersolvents besides benzene that can be used include toluene and xylene. Aslow stream of nitrogen is passed through the system to remove hydrogenbromide formed in the reaction. This reaction can also be carried out at0-25C..

in ether or benzene using an acid acceptor such as pyridine ortriethylamine. I v

In step 2, the l-(bromoacetyl)-7-benzoylindoline (VlIb or VlI'b) isdissolved in a solution of anhydrous ammonia in methanol and thesolutionis allowed to stand at 25C. for 5-l 8 hours to yield I or I.

o Q0 Era-CH8 PROCESS a In this process a 7-benzoylindoline (YIIa orVII'a) is refluxed .with ethyl glycinate hydrochloride and dry pyridinefor 18-24 hours to yield I or I.

In both methods A and B, the products can be. recovered from thereaction mixture by conventional procedures such as crystallization;evaporation, distillation, chromatography and combinations thereof.

10 The 7-benzoylindolines (Vila and Vila) utilized in Processes A andBean be prepared by processes illustrated in F.

Ix Step 1 CH:

NaIOa I Step 2 VII'a VII! wherein R is the same as above.

Thev'l-aminoindolines (IX) used as starting materials in v I Process Fcan be prepared from the appropriately substituted indoline inaccordance with the procedure illustrated by G.

7 1X wherein R is the same as above. The details of this procedure areadequately described by Kost et al., J. Gen. Chem. 29,

3782 (1959). The indolines (XI) utilized in Process G are either readilyavailable or they can be prepared by known methods.

PROCESS C In this process a l,2-dihydro-7-phenylpyrrolo[3,2,I-jk]-['PROCESS D In this process a solution of ethyl benzoylacetate in xyleneis added slowly to a boiling solution of the 7-aminoindoline (VIII) inxylene. During the addition and for an additional 3060 minutes, theethanol and water formed in the reaction are distilled from the mixture.The products formed in the reaction, 1,2-dihydro-6-phenylpyrroloI1,2,3-ef] ['l ,5 benzodiazepin-4(5I-I)-one (IV) andl,2-dihydro-4-phenylpyrrolo-[ l,2,3-ef][I,5]benzodiazepin-6(7I-I)-one(V), can be separated by virtue of their different solubilitycharacteristics.

The starting material (VIII) wherein R is alkyl of from one to threecarbon atoms, inclusive, alkoxy of from one to three carbon atoms,inclusive, bromo, chloro and fluoro can be prepared by a processillustrated by H:

R- R- R- 1101 Zn/NaOH I N Step 1 I f Step 2 I No: +=0 NO: H NH: H

CH: XIV VIII XIII In step 1 a l-acetyl-7-nitroindoline (XIII) isrefluxed with a mixture of 6N hydrochloric acid and ethanol for l-Bhours to give the corresponding 7-nitroindoline (XIV).

In step 2, a stirred refluxing mixture of XIV, ethanol and percentaqueous sodium hydroxide, is treated portionwise with zinc dust at sucha rate that the reflux temperature is maintained without externalheating. Afier the addition, the mixture is refluxed for an additionalhour to yield the corresponding 7-aminoindoline (VIII).

The l-acetyl-7-nitroindolines (XIII) utilized as starting materials (InProcess H) are either readily available or can be prepared by methodswell known in the art.

The compound of formula VIII wherein R is hydrogen can be prepared bythe method described by Gall et al., J. Org, Chem. 20, 1538(1955).

PROCESS E In step 1 of this process, a stirred suspension of1,2-dihydro- 4-phenylpyrrolo[ l,2,3-ef][ 1,5 ]benzodiazepin-6( 7l-I)-one(V) in ether is treated with an excess of 70 percent aqueous perchloricacid and the mixture stirred for an additional 2-5 hours.

In step 2, the product from step I is added to a stirred mixture ofsodium borohydride in ethanol. The mixture is then allowed to stand atambient temperature for 5-18 hours. Thel,2,4,5-tetrahydro-4-phenylpyrrolo[ l,2,3-ef][l,S]benzodiazepin-6(7H)-ones (VI) can be recovered from the reactionmixture by conventional procedures such as crystallization, evaporation,chromatography and combinations thereof.

The acid addition salts of I, Iinvention comprise the salts of thecompounds of formulas I,I', II, III, IV, V and VI and the salts of thecompounds of formulas VII and VII wherein R, is hydrogen withpharmacologically acceptable acids such as sulfuric, hydrochloric,nitric, phosphoric, lactic, benzoic, methanesulfonic, p-toluenesulfonic,salicylic, acetic, propionic, maleic, malic, tartaric, citric,cyclohexanesulfamic, succinic, nicotinic, ascorbic acids and the like.

The novel compounds of this invention exhibit tranquilizing andanticonvulsant activity. Activity was evaluated by use of the followingtests.

CHIMNEY TEST [Med. Exp. 4, l l (1961)] This test determines the abilityof mice to back up and out of a vertical glass cylinder within 30seconds. Failure of mice to back up and out within this time indicatestranquilization.

DISH TEST Mice in Petri dishes (10 cm. diameter, 5 cm. high, partiallyembedded in wood shavings) climb out in a very short time, when nottreated. Mice remaining in the dish for more than 3 minutes indicatestranquilization.

PEDESTAL TEST Mouse is placed on a pedestal. The untreated mouse leavesthe pedestal in less'than a minute to climb back to the floor of thestandard mouse box. Tranquilized mice will stay more than 1 minute.

NICOTINE ANTAGONISM TEST Thirty minutes after mice in a group aretreated with the test compound, both the treated and untreated mice areinjected with 2 mgJkg. of nicotine salicylate. The untreated mice showoverstimulation, i.e. (1) running convulsions followed by (2) tonicextensor fits, followed by (3) death. An effective nicotineantagonistwill protect the treated mice against (2) and (3).

The results of the above tests utilizing some of the novel compounds ofthis invention (administered intraperitoneally) are set forth in thefollowing table. The results are expressed in terms of the mgJkg. dosageat which the tested compounds exhibited the activity in 50 percent ofthe mice (ED *N.A. Nicotine Antagonism TE. Tonic extensor Fits *"*D.Death For purposes of administration to birds and to mammals, includinganimals of economic value such as horses, cattle, sheep, pigs, mice,rats, rabbits and the like, the novel compounds of the. invention can becombined with solid or liquid pharmaceutical carriers and formulated inthe form of tablets, powder packets, capsules and the like solid dosageforms, using starch and like excipients, or dissolved in suitablesolvents or vehicles for oral or parenteral administration.

Also, for mammals and birds food premixes, with starch, oatmeal, driedfishmeat, fishmeal, flour and the like can be prepared. v

The novel compounds of this invention having the formulas I, 1, I1, III,IV, V and V1 and the formulas VII and VII wherein R, is hydrogen alsoform thiocyanic acid addition salts which, when condensed withformaldehyde, form resinous materials useful as pickling inhibitorsaccording to U.S. Pat. No. 2,425,320 and U.S. Pat. No. 2,606,155. Thefluosilicic acid addition salts are useful as mothproofing agentsaccording to U.S. Pat. Nos. 1,915,334 and 2,075,359.

The following examples are set forth to illustrate my invention and toenable persons skilled in the. art to better understand and practice theinvention and are not intended to limit the same.

PREPARATIONS about 2 hours with azeotropic distillation of water. Thesolution is then concentrated under reduced pressure. A solution of theresidue in 20 percent ethanolic sulfuric acid is warmed on the steambath for about 10 minutes; a solid crystallizes from the reactionmixture during this period. The mixture is poured into ice water andstirred for about 45 minutes. The solid is collected by filtration anddried to give 48.3 g. of crude product, melting point l36138C. Thefiltrate is allowed to stand for l8 hours at room temperature. Duringthis time additional product, 6.95 g., melting point 135.5l38C.

precipitates. Crystallization of the combined product from isopropanolgives 50.9 g. of product, melting point l38140.5 C. Recrystallization ofthe product from 95 percent ethanol yields 1,2-dihydro-4-methyl-5-phenyl-pyrrolo[ 3 ,2, 1 -hi]indole, melting point1 39140C. Anal. Calcd. for c,,H,,N: C, 87.51; H, 6.48; N, 6.00.

Found: C, 87.30; H, 6.52; N, 6.00.

Using the procedure described in Preparation A, but replac-' ingl-aminoindoline by the appropriately substituted 1- aminoindoline isproductive of the corresponding 1,2-dihydro- 4-methyl-5-phenylpyrrolo[3,2,1-hi]indole. Representative of the indoles soobtained are: l ,2-dihydro-4,6-dimethyl-5-phenylpyrrolo[ 3 ,2, 1 -hi]indo1e l ,2-dihydro-4,7-dimethyl-5-phenylpyrrolo[3,2,1-hi]indolel,2-dihydro-4,8-dimethyl-5-pheny1pyrrolo[3,2,1 ,-hi]indole l,2-dihydro-8-ethyh4-methyl-5-pheny1pyrrolo[ 3,2, l -hi]indole 1,2-dihydro-8-propyl-4-methyl-5-phenylpyrrolo[ 3 ,2, l

hi]indole l ,2-dihydro-8-isopropyl-4-methyl-5-pheny1pyrrolo[ 3,2, l

hi]indole I l ,2-dihydro-6-methoxy-4-methyl-5-phenylpyrrolo[3,2,1-

1,2-dihydro-7-methoxy-4-methyl-S-phenylpyrrolo[3,2,1-

hi]indole l ,2-dihydro-8-methoxy-4-methyl-5-phenylpyrrolo[ 3,2,1

hi]indole l ,2-dihydro-8-ethoxy-4-methyl-5-phenylpyrrolo[ 3 ,2, 1-

hi]indole l ,Z-dihydro- 8-propoxy-4-methyl-5-phenylpyrrolo[3,2,lhi]indole and l,2-dihydro-8-isopropoxy-4-methyl-5-pheny1pyrrolo[3,2,1-hi]-indo1e.

B. l-ACETYL-7-BENZOYLINDOLINE chloroform extract is washed with water,dried over an-.

hydrous magnesium sulfate and concentrated in vacuo. The residue ischromatographic on 2.2 kg. of silica gel with ethyl acetate; ZOO-ml.fractions are collected. The material eluted in fractions 35-51 iscrystallized from ethyl acetate to give 10.9

0 g. (24.8 percent) of crude product, melting point 142-143C.

The product is recrystallized from ethyl acetate to give 1-acetyl-7-benzoyl-indoline, melting point 142.5C. Anal. Calcd. for C HNQ: C, 76.96; H, 5.70; N, 5.28.

Found: C, 76.89; H, 5.76; N, 5.53. Using the procedure described inPreparation 8, but replacing 1,2-dihydro-4methyl-5-phenylpyrro1o[3,2,1-hi1indole by the appropriatelysubstituted 1,2-dihydro-4-methyI-5-phenylpyrrolo[3,2,l-hi]indole isproductive of the correspondingly substituted1-acety1-7-benzoylindo1ine. Representative of thel-acetyl-7-benzoylindolines so obtained are:

1?acetyl-4-methy1-7-benzoylindoline l-acetyl-5-methyl-7-benzoy1indolinel-acetyl-6-methyl-7-benzoylindoline 1-acetyl-4-ethy1-7-benzoylindoline 9l-acetyl-4-propyl-7-benzoylindoline 1-acety1-4-isopropyl-7-benzoy1indo1inel-acetyl-4-methoxy-7-benzoylindoline l-acetyl-S-methoxy-7-benzoylindoline 1-acetyl-6-rnethoxy-7-benzoylindolinel-acetyl-4-ethoxy-7-benzoylindoline l-acetyl-4-propoxy-7-benzoylindolineand l-acety]-4-isopropoxy-7-benzoylindoline.

C. 7-BENZOYLlNDOLlNE A stirred mixture of 12.6 g. (0.0467 mole) ofl-acetyl-7- benzoylindoline, 380 ml. of 6N hydrochloric acid and 760 ml.of absolute ethanol is refluxed under nitrogen for 5 hours and allowedto stand at room temperature for 18 hours. It is then poured into 4.1.of ice water and the resulting mixture is made ammoniacal. Thecrystalline product is collected by filtration, washed with water, driedand recrystallized from ethyl acetate-Skellysolve B hexanes to give 9.79g. (84.5 percent) of 7-benzoylindoline, melting point l24l 25C.

Anal. Calcd. for C H NO: C, 80.69; H, 5.87; N, 6.27.

Found: C,80.60; H, 5.93; N, 6.47.

Using the procedure described in Preparation C, but replacin gl-acetyl-7-benzoylindoline with the appropriately substitutedl-acetyl7-benzoylindoline is productive of the correspondinglysubstituted 7-benzoylindoline. Representative of the 7-benzoylindolinesso obtained are:

4-methyl-7-benzoylindoline 5-methyl-7-benzoylindoline6-methyl-7-benzoylindoline 4-ethyl-7-benzoylindoline4-propyl-7-benzoylindoline 4-isopropyl-7-benzoylindoline5-methoxy-7-benzoylindoline 4-ethoxy-7-benzoylindoline -benzoylindoline.

4-propoxy-7-benzoylindoline and 4-isopropoxy-7-benxoylindoline.

D. l-(BROMOACETYL)-7-BENZOYLINDOLINE A stirred solution of 2.23 g. (0.01mole) of 7-benzoylindoline (Preparation C) and 0.806 ml. (0.01 mole) ofpyridine in 200 ml. of ether is treated, under nitrogen, with a solutionof 2.24 g. (0.012 mole) of bromoacetyl bromide in a little ether. Theresulting mixture is stirred at room temperature for 2.5 hours andpoured into water. The solid product is collected by filtration, washedwith water, dried in vacuo, and crystallized from ethyl acetate to give2.43 g. of crude product. The ether layer is washed with water, driedover anhydrous potassium carbonate and concentrated. Crystallization ofthe residue from ethyl acetate gives 0.283 g. of additional crudeproduct. The products are combined and recrystallized from ethyl acetateto yield 1-(bromoacetyl)-7- benzoylindoline, melting point 132.5-133C.

Anal. Calcd. for C l-l BrNo z C, 59.32; H, 4.10; N, 4.07; Br, 23.22.

Found: C, 59.71; H, 3.95; N, 4.17; Br, 23.17.

Using the procedure described in Preparation D, but replacing7-benzoylindoline by the appropriately substituted 7- benzoylindoline isproductive of the correspondingly substituted1-(bromoacetyl)-7-benzoylindoline. Representative of thel-(bromoacetyl)-7-benzoylindo1ines so obtained are:

l bromoacetyl )-4-methyl-7-benzoylindoline1-(bromoacetyl)-5-methyl-7-benzoylindoline l bromoacetyl)-6-methyl-7-benzoylindoline 1-( bromoacetyl)-4-ethyl-7-benzoylindolinel bromoacetyl )-4-propyl-7-benzoylindoline 1 bromoacetyl)-4-isopropyl-7-benzoylindoline 1 bromoacetyl)-5-methoxy-7-benzoylindoline 1-( bromoacetyl)-4-ethoxy-7-benzoylindoline 1-(bromoacetyl)-4-propoxy-7-benzoylindoline and l-( bromoacetyl)-4-isopropoxy-7-benzoylindoline.

E. 7-Cl-lLORO- l ,2-DlHYDRO-4-METHYL-5- PHENYLPYRROLO[ 3 ,2, 1 f-hi llNDOLE A stirred mixture of 45.8 g. (0.297 mole) of l-amino-S-chloroindoline, 39.8 g. (0.297 mole) of phenylacetone, 5.91 ml. ofglacial acetic acid and 760 ml. of benzene is refluxed under nitrogenfor 2.5 hours, with azeotropic distillation of water. The resultingsolution is cooled and concentrated under reduced pressure. A solutionof 114.2 g. of concentrated sulfuric acid in 592 ml. of absolute ethanolis added to the residue, and the resulting mixture is heated on thesteam bath for 10 minutes, cooled and poured into ice water. Theproduct, which precipitates during the reaction, is collected byfiltration, washed with water, dried and crystallized from acetone togive 38.0 g. (47.8 percent) of product, melting point 205-206.5C. Theproduct is recrystallized from methyl ethyl ketone to give7-chloro-l,2-dihydro4-methyl-5-phenylpyrrolo[3,2,1-hi]indole, meltingpoint 205.5206.5C.

Anal. Calcd. for C H CIN C, 76.25; H, 5.27; CI, 13.24; N, 5.23.

Found: C, 75.79; H, 5.23; C1, 13.38; N, 4.99.

Using the procedure described in Preparation E, but replacingl-amino-S-chloroindoline with the appropriately substitutedl-amino-haloindoline is productive of the correspondingl,2-dihydro-ha1o-4-methyl-S-phenylpyrrolo[ 3 ,2, l -hi.]indole.Representative of the indoles so obtained are:

6-chloro-1 ,2-dihydro- 8-chlorol ,2-dihydro-6-bromo-l ,Z-dihydro-7-bromol ,Z-dihydro- 8-bromo- 1 ,Z-dihydrol ,2-dihydro-6-fluoro-1,2-dihydro-7-fluroand 1 ,2-dihydro-8-fluoro-4-methyl-5-phenylpyrrolo[ 3,2, l -hi]indole.

F. l-ACETYL-7-BENZOYL-5-CHLORO1NDOLINE A stirred solution of 38.0 g.(0.0142 mole) of 7-chlorol ,2-

dihydro-4-methyl-5-phenylpyrrolo[ 3,2, l -hi]indole (Preparation (E) in1,800 ml. of hot dioxane (7075C.) is treated, under nitrogen, during 1.5hours with a solution of 79.0 g. of sodium metaperiodate in 375 ml. ofwarm water. The resulting mixture is kept at about 70C. for 20 hours,cooled, poured into ice water and extracted several times withchloroform. The combined extracts are washed with water, dried overanhydrous magnesium sulfate and concentrated under reduced pressure.Crystallization of the residue from acetone gives 9.4 g. of startingmaterial. The mother liquor is concentrated and chromatographed on 2 kg.of silica gel with ethyl acetate; ml. fractions are collected. Fractions17-25 are found to contain 7-benzoyl-S-chloroindoline. Fractions 3857are crystal lized from ethyl acetate to give 11.1 g. of product, whichis recrystallized from ethyl acetate to yield l-acetyl-7-benzoyl-5-chloroindoline, melting point 163-164.5C.

Anal. Calcd. for C,-,H,,C1NO,:

C, 68.1 1; H, 4.71; Cl, 11.83; N, 4.67. Found: C, 68.30; H, 4.87; Cl,11.91; N, 4.66.

Using the procedure described in Preparation F, but replacing 7-chloro-1,2-dihydro-4-methyl-5-phenylpyrrolo[3,2,1-hi]- indole with theappropriately substituted 1,2-dihydro-4-methy1-5-phenylpyrrolo[3,2,1-hi]indole is productive of thecorresponding l-acetyl-7-benzoylindoline. Representative of the1-acetyl-7-benzoylindolines so obtained are:

1-acetyl-7-benzoyl-4-chloroindoline lacetyl-7-benzoyle-fi-chloroindolinel-acetyl-7-benzoyl-4-bromoindoline lacetyl-7-benzoyl-5-bromonindolinel-acetyl-7-benzoyl-6-bromonindoline 1-acetyl-7-benzoyl-4-fluoroindoline1-acetyl-7-benzoyl-5-fluoroindoline andl-acetyl-7-benzoyl-6-fluoroindoline.

A stirred mixture of 1.95 g. (0.00652 mole) of 1-acetyl-7-benzoyl--chloroindoline (Preparation F), 33.3 ml. of absolute ethanoland 16.7 ml. of 6N hydrochloric acid is refluxed under nitrogen for 4hours, cooled and poured into ice water. The resulting mixture is madealkaline with 50 percent aqueous sodium hydroxide. The yellow,crystalline product is collected by filtration, washed with water anddried to give 1.65 g. (98.6 percent) of crude product. The product isrecrystallized from ethyl acetate-Skellysolve B hexanes to yield 7-benzoyl-S-chloroindoline, melting point 123-l23.5C.

Anal. Calcd. for C,,,H,,C1NO:

C, 69.90; H, 4.70; Cl, 13.76; N, 5.44.

Found: C, 69.59; H, 4.82; Cl, 13.83; N, 5.83.

Using the procedure described in Preparation G, but replacingl-acetyl-7-benzoyl-5-chloroindoline by the appropriately substituted1-acetyl-7-benzoylindoline is productive of the correspondinglysubstituted 7-benzoylindoline. Representative of the 7-benzoylindolinesso obtained are:

7-benzoyl-4-chloroindoline 7-benzoyl-6-chloroindoline7-benzoyl-4-bromoindoline 7-benzoyl-S-bromonindoline7-benzoyl-6-bromonindoline 7-benzoyl-4-fluoroindoline7-benzoyl-S-fluoroindoline and 7-benzoyl-6-fluoroindoline.

H. 7-BENZOY L- l BROMOACETYL)-5- CHLOROINDOLINE A stirred mixture of1.50 g. (5.83 millimoles) of 7-benzoyl- 5-chloroindo1ine (PreparationG), 50 ml. of benzene and 2.35 g. 1 l .7 millimoles)"of bromoacetylbromide is refluxed for 45 minutes with a slow stream of nitrogenflowing through the system to flush out the hydrogen bromide formed. Themixture is cooled in an ice bath and diluted with 50 ml. of SkellysolveB hexanes. The crystalline material is collected by filtration, washedwith Skellysolve B hexanes and recrystallized from ethylacetate-Skellysolve B hexanes to give 1.73 g. (78.3 percent) of product.Additional product, 0.269 g., is obtained by concentrating thebenzene-Skellysolve B hexanes'filtrate and crystallizing the residuefrom ethyl acetate-Skellysolve B hexanes. The two crops are combined andrecrystallized from ethyl acetate-Skellysolve B hexanes to yield7-benzoyl-1- (bromoacetyl)-5-chloroindoline, melting point l65.5-l66.5DC I 7 Anal. Calcd. for C,-,l-l BrClNO,:

C, 53.92; H, 3.46; Br, 21.1 1; Cl, 9.36; N, 3.70.

. Found: C, 54.17; H, 3.71; Br, 21.04; Cl, 9.43; N, 3.69.

Using the procedure described in Preparation H, but replacing7-benzoyl-5-chloroindoline with the appropriate 7- benzoyl-haloindolineis productive of the corresponding 7-benzoyl-1-(bromoacetyl)-haloindoline. Representative of thehaloindolines so obtained 'are:

7-benzoyll bromoacetyl)-4-chloroindoline 7-benzoyl- 1bromoacetyl)-6-chloroindoline 7-benzoyl- 1 bromoacetyl)-4-bromoindoline7-benzoyl- 1 bromoacetyl )-5-bromoindoline 7-benzoyl- 1 bromoacetyl)-6-bromoindoline 7 -benzoyl- 1 bromoacetyl )-4-fluoroindoline7-benzoyl- 1 bromoacetyl)-5-fluoroindoline and 7-benzoyl- 1 bromoacetyl)-6-fluoroindoline.

I. l-ACETYL-7-BENZOYL-5-NlTROlNDOLlNE A stirred mixture of 21.8 g.(0.0823 mole) of 1-acetyl-7- benzoylindoline (Preparation B), 82.3 ml.of acetic anhydride and 41 ml. of acetic acid is cooled to 10C. andtreated during minutes with 8.64 reactants (0.123 mole) of 90 percentnitric acid. The temperature is kept below 13C. during the addition. Thereaction mixture is allowed to warm slowly to ambient temperature during4.5 hours and is then poured into ice water. This mixture is stirred for30 minutes, and the solid is collected by filtration, washed with waterand dried in vacuo. Crystallization of this solid from ethanol-methylenechloride gives 21.5 g. (84.2 percent) of crude product.Recrystallization of the crude product from ethanolmethylene chloridegives 1-acetyl-7-benzoyl-5-nitroindoline, melting point 200-201C.

Anal. Calcd. for C H,,N,0,:C, 65.80; H, 4.55; N, 9.03.

Found: C, 65.73; H, 4.60; N, 8.81.

.l. 7-BENZOYL-5-N1TROINDOLINE A stirred mixture of 9.30 g. (0.030 mole)of 1-acetyl-7- benzoyl-S-nitroindoline (Preparation 1), ml. of 6Nhydrochloric acid and 300 ml. of ethanol is refluxed under nitrogen for1 hours. As the reaction proceeds the reactants slowly go into solutionand a solid precipitates as feathery, yellow crystals. The resultingmixture is cooled, poured into ice water and neutralized with 50 percentaqueous sodium hydroxide. The solid is collected, washed with water, anddried in vacuo to give 7.84 g. (87,3 percent) of crude product. Thisproduct is recrystallized from ethyl acetate to yield 7-benzoyl-5-nitroindoline, melting point 223224C.

Anal. Calcd. for C, -,H,,N,O,: C, 67.15; H, 4.51; N, 10.44.

Found: C, 66.65; H, 4.39; N, 10.25.

K. 7-BENZOYL-1-(BROMOACETYL)-5-NlTROlNDOLlNE A stirred mixture of 4.51g. (0.0168 mole) of 7benzoyl-5- nitroindoline (Preparation .1), 6.78 g.(0.0337 mole) of bromoacetyl bromide and ml. of benzene is refluxed for2.5 hours. During the reaction a slow stream of nitrogen is allowed topass through the system to flush out the hydrogen bromide formed. Thereaction mixture is cooled in an ice bath and diluted with 200 m1. ofSkellysolve B hexanes. The solid product is collected by filtration andrecrystallized from ethyl acetate to give 5.90 g. of crude product. Thisproduct is again recrystallized from ethyl acetate to give 7-benzoyl-1-(bromoacetyl)-5-nitroindoline, melting point 169-1 7 1C. Anal. Calcd.for C H,,BrN,O,:

C, 52.46; H, 3.37; Br, 20.53; N, 7.20.

Found: C, 52.38; H, 3.36; Br, 20.46; N, 6.78.

L. l-ACETYL-5-CHLORO-7-NITROINDOLINE A stirred mixture of 66.9 g. (0.342mole) of l-acetyl-S- chloroindoline, 342 ml. of acetic anhydride and 136ml. of

acetic acid is cooled to 1015C. and treated during 15 minutes with asolution of 35.9 g. of fuming nitric acid in 34.2 ml. of aceticacid.'The mixture is kept at 1015C. during the addition and for anadditional 2 hours. It is then poured into cold water. The solid iscollected by filtration, washed with water, dried and recrystallizedfrom ethyl acetate to give two crops of crude product, 71.1 g., meltingpoint 173.5-176C., and 4.12 g., melting point 170-l73.5C. (91.4percent). Recrystallization of this product from ethyl acetate yields 1-acetyl-S-chloro-7-nitroindoline, melting point 174-1 75C. Anal. Calcd.for C,,,H,C1N,O,:

C, 49.91; H, 3.77; N, 11.64; C], 14.74.

Found: C, 50.22; H, 4.07; N, 11.61 Cl, 14.75.

Using the procedure described in Preparation L, but replacing1-acetyl-5-chloroindoline by the appropriately substitutedl-acetylindoline is productive of the corresponding l-acetyl'7-nitroindoline. Representative of thel-acetyl-7-nitroinl-acetyl-5-isopropyl-7- 1-acetyl-5-ethoxy-7- M.-CHLORO-7-NITRO1NDOL1NE A stirred mixture of 3.62 g. (0.015 mole) ofl-acetyl-S- chloro-7-nitroindoline (Preparation L), 50 ml. of 6Nhydrochloric acid and 100 ml. of ethanol is refluxed under nitrogen for2 hours, and allowed to stand at ambient temperature for 18 hours. Thereaction mixture which contains crystalline product is poured intowater. The solid is collected by filtration, washed with water, driedand recrystallized from ethyl acetate to give 2.67 g. (89.7 percent) ofproduct. This product is recrystallized again from ethyl acetate to give5- chloro-7-nitroindoline, melting point 125-126C.

Anal. Calcd. for C H,ClN,O

C, 48.37; H, 3.55; N, 14.1 1; Cl, 17.85.

Found: C, 48.42; H, 3.67; N, 14.19; Cl, 18.02.

Using the procedure described in Preparation M, but replacingl-acetyl-5-chloro-7-nitroindoline by the appropriately substitutedl-acetyl-7-nitroindoline is productive of the corresponding7-nitroindoline. Representative of the 7- nitroindolines so obtainedare:

5-bromo-7-nitroindoline 5-methyl-7-nitroindoline 5-ethyl-7-nitroindoline5-propyl-7-nitroindoline 5-isopropyl-7-nitroindoline5-methoxy-7-nitroindo1ine 5-ethoxy-7-nitroindo1ine5-propoxy-7-nitroindoline and 5-isopropoxy-7 -nitroindoline.

N. 7-AMINO-5-CHLORO1NDOLINE AND HYDROCHLORIDE THEREOF A stirred mixtureof 19.9 g. (0.10 mole) of 5-chloro-7- nitroindoline (Preparation M), 52ml. of 95 percent ethanol and 8 ml. of 20 percent aqueous sodiumhydroxide is warmed under nitrogen to the reflux temperature andtreated, portionwise, with 26 g. of zinc dust at such a rate that themixture refluxes without external heating. At the end of the addition,the mixture has changed from red to light yellow. Additional ethanol (13ml.) is added and the mixture is refluxed for 1 hour, cooled andfiltered. The solid is washed with ether. The combined filtrate andwashing is treated with l g. of sodium hydrosulfite and concentrated invacuo. A suspension of the residue in water is extracted with ether. Theextract is washed with a saturated solution of sodium chloride, driedover anhydrous potassium carbonate and concentrated in vacuo to yield7-amino-5-chloroindoline as a residue.

A solution of the residue in ethanol is cooled in an ice bath andacidified with methanolic hydrogen chloride. The resulting crystallinesolid is collected by filtration and washed with ethanol. A small amountof additional product is obtained by concentrating the filtrate. Thecombined product is recrystallized to give 10.6 g., melting point 222C.(dec.), and 0.849 g., melting point 219.5-221C. (dec.), of product.Recrystallization of this product from ethanol yields7-amino-5-chloroindoline hydrochloride, melting point 21 8.5-220C.(dec.). Anal. Calcd. for C H ClN -HCh C, 46.85; H, 4.91;Cl, 34.58;N,13.66.

Found: C, 46.85; H, 4.88; C], 34.80; N, 13.51.

Using the procedure described in Preparation N, but replacing5-ch1oro-7-nitroindoline by the appropriately substituted7-nitroindoline is productive of the corresponding 7-aminoindoline.Representative of the 7-aminoindolines so obtained are:

7-amino-5-bromoindoline 7-amino-5-fluoroindoline7-amino-5-methylindoline 7-amino-5-ethylindoline7-amino-5-propylindoline 7-arnino-5-isopropylindoline7-amino-5-methoxyindoline 7-amino-5-ethoxyindoline 7-amino-5-propoxyindoline and 7-amino-S-isopropoxyindoline.

EXAMPLE 1 1,Z-DIHYDRO7-PHENYLPYRROLOl 3,2, 1- jk][ 1 ,4]BENZOD1AZEPlN-4-( 5 H )-ONE A solution of 1.0 g. (0.00299 mole) of1-(bromoacetyl)-7- benzoylindoline (Preparation D) in ml. oftetrahydrofuran is mixed with 36 ml. of a 13 percent solution of ammoniain methanol, and the resulting solution is stirred at room temperature,under nitrogen, for 19 hours. It is then concentrated under reducedpressure at 25C. The residue is mixed with water and extracted withmethylene chloride. The extract is dried over anhydrous potassiumcarbonate and concentrated. Crystallization of the resulting productfrom ethyl acetate- Skellysolve B hexanes gives 0.63 g. of crudeproduct. This product is recrystallized from ethyl acetate-Skellysolve Bhexanes to give l,2-dihydro-7-phenylpyrrolo[3,2,1-jk][l,4]benzodiazepin-4(5l-l)-one, melting point l41.5C. Anal. Calcd. for CH N O: C, 77.84; H, 5.38; N, 10.68.

Found: C, 77.90; H, 1,N, 10.83.

Using the procedure described in Example 1, but replacing1-(bromoacetyl)-7-benzoylindoline by the appropriately substituted1-(bromoacetyl)-7-benzoylindoline is productive of the correspondinglysubstituted 1,2-dihydro-7-phenylpyrrolo-[3,2,1-jk][l,4]benzodiazepin-4-(5H)-one. Representative of thel,2-dihydro-7-phenylpyrrolo[ 3,2, l -jk][ 1,4]benzodiazep in-( 5H)-onesso obtained are:

l ,2-dihydro-8-methyl- 1 ,Z-dihydroS-methyl- 1,2-dihydrol O-methyll,2-dihydro-9-ethyll ,2-dihydro-9-propyll ,2-dihydro-9-isopropyl- 1,2-dihydro-8-methoxy- 1 ,2-dihydro-9-methoxy- 1 ,2-dihydrol O-methoxy- 1,2-dihydro-9-ethoxy- 1,2-dihydro-9-propoxyand l,2-dihydro-9-isopropoxy-7-phenylpyrrolo[ 3,2, l -jk][ 1 ,4]benzodiazepin-4-(5H)-ones.

Example 2 9-CHLORO-l ,2-DlHYDRO-7- PHENYPYRROLO[3,2,11,4]BENZODlAZEPIN-4- (5 H)-ONE A solution of 13.5 g. (0.0357 mole) of7-benzoyl-l- (bromoacetyl)-5-chloroindo1ine (Preparation H) in 525 ml.of tetrahydrofuran is treated with 450 ml. of methanol that has beensaturated at room temperature with anhydrous ammonia. This solution isstirred, under nitrogen, at room temperature for 18 hours andconcentrated under reduced pressure at 20-25C. The residue is suspendedin water and extracted several times with methylene chloride. Theextract is dried over anhydrous potassium carbonate and concentratedunder reduced pressure. Crystallization of the residue from ethylacetate-Skellysolve B hexanes gives 6.32 g. of a first crop of productand 2.37 g. of a second crop. Recrystallization of this product fromethyl acetate-Skellysolve B hexanes yields 9-chlor-1,2-dihydro-7-phenylpyrrolo[3,2,1-jk][ 1 ,4]benzodiazepin-4-(5H)-one, melting point 1 l6-1 17.5C.

Anal. Calcd. for C,,H,,C|N,0;

C, 68.80; H, 4.41; Cl, 1 1.95; N, 9.44.

Found: C, 68.98; H, 4.50; C], 11.94; N, 9.24.

Using the procedure described in Example 2, but replacing7-benzoyl-l-(bromoacetyl)-5-chloroindoline with the appropriate7-benzoyl-1-(bromoacetyl)-haloindoline is productive of thecorresponding 1,Z-dihydro-haloJ-phenylpyrrolo[3,2,1-jk]-[1,4]benzodiazepin-4-(51-l)-one. Representative of thebenzodiazepin- 4(5l-l)-ones so obtained are:

8-chloro-l ,2-dihydro-7-phenylpyrrolo- 10-chlorol,2-dihydro-7-phenylpyrrolo- 8-bromol ,2-dihydro-7-phenylpyrrolo-9-bromo-1 ,2dihydro-7-phenylpyrrololO-bromo-1,2-dihydro-7-phenylpyrrolo- 8-fluoro-1,2-dihydro-7-phenylpyrrolo- 9-fluoro-l ,2-dihydro-7-phenylpyrroloand lO-fluorol ,2-dihydro-7-phenylpyrrolo[3,2,1-jk][ 1,4 ]benzodiazepin-'4(5H )-ones.

EXAMPLE 3 1,2-DIHYDRO-9-NITRO-7- PHENYLPYRROLO[ 3 ,2, l f-jk][ l,4J-BENZODIAZEP1N- 4( 5H )-ON E A stirred suspension of 3.89 g. (0.01mole) of 7-benzoyl-1- (bromoacetyl)-5-nitroindoline (Preparation K) in150 ml. of

dry tetrahydrofuran is cooled in an ice bath and treated with amethylene chloride solution is washed with water, dried over anhydrousmagnesium sulfate and concentrated. The residue is chromatographed on200 g. of silica gel with 50 percent ethyl acetate-50 percentcyclohexane (by volume); 50-m1. fractions are collected. The materialeluted from the column in fractions 35-63 is crystallized from ethylacetate-Skellysolve B hexanes to give 0.199 g.,melting point l57.5l60C., and 0.067 g., melting point 157158.5C., of product.

The twocrops of product are combined and recrystallized from ethylacetate-Skellysolve B hexanes to give 1,2 -dihydro-9-nitro-7-phenylpyrrolo[ 3,2, l -jk][ 1,4]benzodiazepin-4(5H)- one,melting point l57l 58.5C'.

Anal. Calcd. for C H,,N,O,: C, 66.44; H, 4.26; N, 13.68.

Found: C, 66.53; H, 4.55; N, 13.63. 7

EXAMPLE 4 1,2-DIHYDRO-9-NlTRO-7- PHENYLPYRROLO[ 3,2,lf-jk][1,4]-BENZOD1AZEP1N- 4( 5H )-ON E A stirred mixture of 5.18 g.(0.0194 mole) of 7-benzoyl-5- nitroindoline (Preparation J), 5.40 g.(0.0387 mole) of ethyl glycinate hydrochloride and 40 ml. of pyridine isrefluxed under nitrogen for 24 hours. During the first 6 hoursaPyridine-water-ethanol azeotrope (50 ml.) is slowly distilled from thereaction mixture and replaced 'with fresh dry pyridine. The cooledreaction mixture is concentrated under reduced pressure. A littletoluene is added to the residue, and the resulting mixture is againconcentrated. This residue is suspended in cold water, made ammoniacaland extracted with methylene chloride. The extract is washed with water,

dried over anhydrous potassium carbonate, treated with 35 g. 50

of silica gel and concentrated under reduced pressure. The residue ispoured onto a column of silica gel (250 g.) which has been prepared with60 percent ethyl acetate-40 percent cyclohexane (by volume). The columnis then eluted with 60 percent ethyl acetate-40 percent cyclohexane;40-ml. fractions are collected. The material eluted in fractions 28 tothe end contains the product. The product is crystallized from ethylacetate-Skellysolve B hexanes in two crops; 2.82 g., melting pointl60-l63.5C. andthe other 0.258 g., melting point 159.5-162.5C. (51.5percent yield) of 1,2-dihydro-9- 60 nitro-7-phenylpyrro1o[3,2,l-jk][ l,4]benzodiazepin-4(5H)- one which has a nmr spectran identical to theproduct obtained in Example 3.

EXAMPLE 5 6,7-DlHYDRO-7-PHENYLPYRROLO[ 3,2, l J' 1 -BENZODlAZEPlN-4( 5H)-ONE AND 7- PHENYLPYRROLO[ 3 ,2, lf-jlt] l,4]BENZODlAZEPlN-4( 5H)-ONEa. Mixture of 6,7-dihydro-7-phenylpyrrolo[3,2,l-jk]- l,4]benzodiazepin-4(5H)-one and 7-phenylpyrrolo- [3,2, l -jk][ l,4]benzodiazepin-4(5H)-one tion. The resulting mixture is cooled,treated with 5.24 g. (0.02 mole) ofl,2-dihydro-7-phenylpyrroloI3,2,1-jk][ l,4]benzodiazepin-4(5H)-one(Example 1), refluxed under nitrogen for 1,5 hours, cooled and filtered.The solid is washed with about 50 ml. of ethyl acetate and the ethylacetate solution is concentrated to dryness. The residue is combinedwith the decalin filtrate and poured onto a silica gel (400 g.) columnwhich has been prepared with cyclohexane. The material is washed ontothe column with cyclohexane and the column is eluted with 15percent'ethyl acetate percent cyclohexane (by volume) (fractions 1-60)and ethyl acetate (fractions 61-82); 75-ml. fractions are collected.

b. 7-Phenylpyrrolo[3,2,1-jk][ l,4]benzodiazepin-4(5H)'one The materialeluted in fractions 23-33 is crystallized from ethyl acetate-SkellysolveB hexanes to give 0.714 g. of product, melting point l49.5-l50.5C. Thisproduct is recrystallized from ethyl acetate-Skellysolve B hexanes toyield 7-phenylpyrrolo[3,2,1-jk][ 1 ,4]benzodiazepin-4(5 H one, meltingpoint 15 1.5-l52C.

Anal. Calcd. for C,,H,,N,O: C, 78.44; H, 4.65; N, 10.76.

Found: C, 78.77; H, 4.96; N, 10.62.

Using the procedure describedin Example 5 (a and b), but replacingl,2-dihydro-7-phenylpyrrolo[ 3 ,2, l -jk][ l,4]benzodiazepin-4(5H)-oneby the appropriately substitutel,2-dihydro-7-pheny1pyrrolo[3,2,l-jk][1,4]benzodiazepin-4 (5H)-0nes isproductive of the corresponding 7-phenylpyrrolo[ 3,2, 1 -jk][1,4]-benzodiazepin-4( 5H)-ones. Representative of the7-phenylpyrrolo[3,2,l-jk][l,4]benzodiazepin-4(5 H)-ones so obtained are:

9-methyl-7-phenylpyrrolo- 9-ethyl-7-phenylpyrrolo--7-phenyl-9-propylpyrrolo- 9-isopropyl-7-pheny1pyrrolo-9-methoxy-7-phenylpyrrolo- 9-ethoxy-7-phenylpyrrolo-8-methyl-7-phenylpyrrolo-8-methoxy-7-phenylpyrrolol0-methyl-7-phenylpyrroloand l0-methoxy-7-pheny1pyrrolo[ 3,2, l -jk] l ,4]benzodiazepin- 4(5H)-ones.

c. 6,7-Dihydro-7-phenylpyrrolo[3,2,-1-jk][1,4]benzodiazepin- Thematerial eluted in fractions 36-58 is crystallized from ethylacetate-skellysolve B hexanes to give 1.00 g., melting point 114-1l6C.and 0.246 g., melting point ll2.5-l14C. of product. Recrystallization ofthis product from ethyl acetate-Skellysolve B hexanes gives6,7-dihydro-7-phenylpyrrolo[3,2, l -jk][ l ,4]benzodiazepin-4(5H)-one,melting point l15-l 17C.

Anal. Calcd. for C, H N,O: C, 77.84; H, 5.38; N, 10.68.

Found: C, 77.60; H, 5.31; N, 10.47.

Using the procedure described in Example'5 (a and 0), but replacing l,2-dihydro-7-phenylpyrrolo[ 3 ,2, l-jk][ 1,4]benzodiazepin-4( 5H)-one bythe appropriately substituted l,2-dihydro-7-phenylpyrrolo[ 3,2, l -jk][l,4]benz0diazepin-4(5H)-ones is productive of the cor-' responding6,7-dihydro-7-phenylpyrroloI 3,2,1-jk][ l,4]benzodiazepin4(5H)-ones.Representative of the 6,7- dihydro-7-phenylpyrrolo[ 3,2, l -jk][ l,4lbenzodiazepin-4 (5H)-ones so obtained are:

0 6,7-dihydro-7-phenyl-9-propylpyrro1o- Water is removed from a mixtureof 10 percent palladium- 75 on-carbon catalyst (2.6 g.) and decalin ml.)by distilla- 6,7-dihydro-9-isopropyl-7-phenylpyrrolo-6,7-dihydro-9-methoxy-7-phenylpyrrolo- 6,7-dihydro-9-ethoxy-7phenylpyrrolo- 6,7-dihydro-8-methyl-7-phenylpyrrolo- 6,7-dihydrolO-methyl- 7-phenylpyrrolo- 6,7-dihydro-8-methoxy-7-phenylpyrroloand6,7-dihydro-10-methoxy-7-phenylpyrrolo[3,2,1-jk][ 1,4 ]benzodiazepin-4(H )-ones.

EXAMPLE 6 9-Cl-1LORO-1,2-DlHYDRO-6- PHENYLPYRROLO[ l,2,3-ef]-1,5]BENZODlAZEPIN-4(5H)-ONE AND 9-CHLORO-1,2-

l,2-dihydro-4-phenylpyrrolo[1,2,3-ef][1,5]benzodiazepin- 6( 7H)-one Asolution of 2.05 g. (0.01 mole) of 7-amino-5-chloroindolinehydrochloride (Preparation N) in cold water is made alkaline with sodiumhydroxide and extracted with ether. The extract is washed with brine,dried over anhydrous sodium carbonate and concentrated in vacuo. Asolution of the residue in xylene (20 ml.) is heated to the refluxtemperature, under nitrogen, and treated during 26 minutes with asolution of ethyl benzoylacetate (1.92 g.; 0.01 mole) in xylene ml.).During the addition and for an additional 36 minutes ethanol and waterformed in the reaction are distilled from the mixture; the volume iskept constant by the addition of fresh xylene (9.5 ml.). The mixture iscooled and diluted with Skellysolve B hexanes. The solid product iscollected by filtration, washed with Skellysolve B hexanes and extractedwith ether.

b. 9-Chloro-1,2-dihydro-4-phenylpyrrolo[1,2,3-ef][1,5]- benzodiazepin-6(71-1 )-one The solid remaining after the ether extraction [Example 6(a)] is dissolved in methylene chloride-methanol, decolorized withdecolorizing carbon and crystallized to give 0.299 g., melting point279-282C., and 0.043 g., melting point 277281C. (11.5 percent yield) ofproduct. Recrystallization of this product from methylene chloride gives9-chloro- 1 ,Z-dihydro-4-pheny1pyrrolo[ 1,2,3-ef][1,5]benzodiazepin-6(7H)-one, melting point 280-281C.

Anal. Calcd. for C, H, CIN O:

C, 68.80; H, 4,41; Cl, 11.95; N, 9.44.

Found: C, 69.14; H, 4.89; Cl, 12.06; N, 8.95.

Using the procedure of Example 6 (a and b), but replacing7-amino-5-chloroindoline hydrochloride by the appropriately substituted7-aminoindoline hydrochlorides is productive of the corresponding1,2-dihydro-4-phenylpyrrolo[ 1,2,3-ef][ l,5]benzodiazepin-6(7H)-ones.Representative of the 1,2- dihydro-4-pheny1pyrrolo[ 1 ,2,3-ef][ 1,5]benzodiazepin-6 (7l-1)-ones so obtained are:

1,2-dihydro-4-phenylpyrrolo- 9-bromo-l ,2-dihydro-4-phenylpyrrolo-9-fluoro- 1 ,2-dihydro-4-phenylpyrrolo- 9-methyl-l,2-dihydro-4-phenylpyrrolo- 9-ethyl-1,2-dihydro-4-phenylpyrrolo-9-propyll ,2-dihydro-4-phenylpyrrolo- 9-methoxyl,2-dihydro-4-phenylpyrrolo- 9-ethoxyl ,2-dihydro-4-pheny1pyrroloand9-propoxy-1,2dihydro-4-phenylpyrrolo[ 1 ,2,3-ef][ 1,5 ]benzodiazepin-6(7H)-ones.

c. 9-Ch1orol ,2-dihydro-6-phenylpyrrolo[ l ,2,3-ef][ 1,5benzodiazepin-4( 5H)-one The ether extract from Example 6 (a) isdecolorized with C, 68.80; H. 4.41; CI, 11.95; N, 9.44.

Found: C, 69.02; H, 4.64; CI, 12.14; N, 9.44.

Using the procedure of Example 6 (a and c), but replacing7-amino-5-chloroindoline hydrochloride by the appropriately substituted7-aminoindoline hydrochlorides is productive of the corresponding1,2-dihydro-6-phenylpyrrolo{ 1,2,3-ef][ l,5]benzodiazepin-4(5H)ones.Representative of the 1,2- dihydro-6-phenylpyrrolo[ 1,2,3-ef][ 1 ,5]benzodiazepin-4 (5l-1)-ones so obtained are:

9-bromo-1,2-dihydro-6-phenylpyrrolo- 9-methy1-l,2-dihydro-6-phenylpyrrolo- 9-ethyl- 1 ,2-dihydro-6-phenylpyrrolo-9-propy1-1 ,2-dihydro-6-phenylpyrrolo- 9-methoxy-1,2-dihydro-6-phenylpyrrolo- 9-ethoxy-1,2-dihydro-6-phenylpyrroloand9-propoxy- 1 ,2dihydro-6-phenylpyrrolo[ 1,2,3-ef][ 1,5]benzodiazepin-4(5l-l)-ones.

EXAMPLE 7 9-CHLORO- l ,2-Dll-lYDRO-4- PHENYLPYRROLO[1,2,3-ef]- 1,5]BENZODIAZEPlN-6( 7H )-ONE PERCHLORATE A suspension of 2.0 g. of9-chloro-l,2-dihydro-4pheny1pyrro1o[l,2,3-ef][1,5]ben2odiazepin-6(7H)-one [Example 6 (b)]n about 25 ml. ofether and 3 ml. of percent perchloric acid is stirred for 2 hours. Thesolid is collected by filtration, washed with ether and dried to give2.47 g. of crude product, melting point 263-267C. (dec.). This productis recrystallized from methanol-ethyl acetate to give 9-chloro-l,2-dihydro-4-pheny1pyrrolo[ 1 ,2,3-ef][ 1,5 ]benzodiazepin- 6(7l-1)-oneperchlorate, melting point 270C.

Anal. Calcd. for C, H, C1N O'11C1O,:

C, 51.40; H, 3.55; Cl, 17.85; N, 7.05.

Found: C, 51.23; H, 3.54; Cl, 18.05; N, 6.88.

Using the procedure of Example 7, but replacing 9-chloro-1,2-dihydro-4-phenylpyrrolol l ,2,3ef] l ,5 ]benzodiazepin 6(7l-1)-oneby the appropriately substituted 1,2-dihydro-4- phenylpyrrolo[1,2,3-ef][ 1 ,5 ]benzodiazepin-6( 71-1 )-ones is productive of thecorresponding 1,2-dihydro-4-phenylpyrrolol l,2,3-ef][1,5]benzodiazepin-6(7H)-one perchlorates. Representative of theperchlorates so obtained are the perchlorates of thel,2-dihydro-4-phenylpyrrolo[ l,2,3-ef]{ l,5]benzodiazepin-6(7H)-ones set6 in Example 6 (b).

EXAMPLE 8 9-CHLORO-4-PHENYL-l,2,4,5- TETRAHYDROPYRROLO[ 1,2,3-ef][1,5]BEN ZODIAZEPlN-6( 7H)-ONE A stirred mixture of 2.5 g. of sodiumborohydride in absolute ethanol is cooled in an ice bath and treated,portionwise, with 2.51 g. of 9-chloro-1,2-dihydro-4-phenylpyrrolo[1,2,3-ef][ 1 ,5]benzodiazepin-6(7H)-one perchlorate (Example 7). Themixture is allowed to warm slowly to ambient temperature and stand for22 hours under nitrogen. It is then concentrated in vacuo. The residueis mixed with water, stirred in an ice bath for a few minutes andfiltered. The solid is washed with water, dried and recrystallized fromethyl acetate to give 1.24 g. (65.6 percent) of a mixture of polymorphsof the desired product, melting point 153.5-l93.5C. Recrystallizing themixture from ethyl acetate yields the higher melting polymorph of9-chloro-4-phenyl-1,2,4,5-tetrahydropyrrolo-1,2,3-ef][1,5]benzodiazepin-6(71-1)-one, melting point 183-187C.

Anal. Calcd. for C,-,H,,,C1N,O:

C, 68.34; H, 5.06;C1,11.87;N, 9.38.

decolorizing carbon and crystallized to give 1.31 g. (44.3 per- 70Found: C, 68.26; H, 5.10; Cl, 1 1.79; N, 8.98.

cent) of product, melting point 123-126C. This product is recrystallizedfrom ether to yield 9-chloro-1,2-dihydro-6- phenylpyrrolo-[ l ,2,3-ef] l,5 ]benzodiazepin-4( 5l-1)-one, melting point 124.5-125.5C.

Anal. Calcd. for cnH aciNzoi Using the procedure described in Example 8,but replacing 9-chlorol ,2-dihydro-4-phenylpyrrolo[ 1,2,3-ef][ 1,5]benzodiazepin-6(7H)-one perchlorate by the appropriately substituted 1,2-dihydro-4-phenylpyrrolo[ l ,2,3-ef][ l,5]benzodiazepin-6(7H)-oneperchlorates is productive of VII VII wherein R is selected from thegroup consisting of hydrogen, alkyl of from one to three carbon atoms,inclusive, alkoxy of from one to three carbon atoms, inclusive, bromo,chloro and fluoro; R, is selected from the group consisting of hydrogen,acetyl and bromoacetyl; and

b. the acid addition salts with pharmacologically acceptable acids ofthe compounds of the above formulas wherein R, is hydrogen.

2. A compound of claim I having the formula of VI].

3. A compound of claim 2 wherein R and R, are hydrogen.

4. A compound of claim 2 wherein R is hydrogen and R, is

acetyl.

5. A compound of claim 2 wherein R is hydrogen and R, is

bromoacetyl.

6. A compound of claim 2 wherein R is 5-chloro and R, is

hydrogen.

7. A compound of claim 2 wherein R is 5-chloro and R, is

acetyl.

8. A compound of claim 2 wherein R is 5-chloro and R, is

bromoacetyl.

9. A compound of claim 1 having the formula of VII.

10. A compound of claim 9 wherein R, is hydrogen.

11. A compound of claim 9 wherein R, is acetyl.

12. A compound of claim 9 wherein R, is bromoacetyl.

UNTTEIT TKTESTAT v oFFIcEi CERTIFICATE OF CORRECTION Patent No. 5, 79,7Dated y 5, 97

Inventor(s) Jackson B. Hester.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 2, line 11, For read A) Column line 10, for (Vi la and Vi l 'a)"read (VI la and VI! 'a) Column 6,, l ine 16, for "of l ,I 'invention"read of the invention Column 7, l i ne 55, for 32 I read 79 32 Column 9,line 35, for. "benzoylindoline-benzoylindollne." read benzoylindolineColumn 9', line 37, for "benxoflindollne." read benzoyl indoli ne Column10, linec2, -for 5,2,1f-hr1" read [3,2,1-hi] Column 10, line 41, for"(70 75 c.)" read (70-75 0.) Column 11, line 71, for reactants" read g.Column 14, l ine 21, for "H, 1," I read H, 5.29; Column 14, l i he l -l,for "5,2,1]-[" read .5,2,1-j k] Column 15, l lne 8, for [3,2,1f-j k1"read [5,2,1-j k] Colurr 15, l ine 36, for [5,2,1f-j kl" read [32,1 k]Column 15, l l ne 68, for [5,2,1f-j k1" read [3,2,1-j k] Column 16,

line 26, for "substitute" read substituted Column 17, line 5 for re 4,EQlemnifi el jei ie f "0" read n Column 18 line 46, "6", firstoccurrence,

should read forth Signed and sealed this 6th day of March 1973 v (SEAL)Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer a Commissionerof Patents FORM PC4050 (10-69) USCOMM DC 603764369 u.s. eovznumzm'rmrmue ornc: I969 o-ass-zu

2. A compound of claim 1 having the formula of VII.
 3. A compound ofclaim 2 wherein R and R2 are hydrogen.
 4. A compound of claim 2 whereinR is hydrogen and R2 is acetyl.
 5. A compound of claim 2 wherein R ishydrogen and R2 is bromoacetyl.
 6. A compound of claim 2 wherein R is5-chloro and R2 is hydrogen.
 7. A compound of claim 2 wherein R is5-chloro and R2 is acetyl.
 8. A compound of claim 2 wherein R is5-chloro and R2 is bromoacetyl.
 9. A compound of claim 1 having theformula of VII''.
 10. A compound of claim 9 wherein R2 is hydrogen. 11.A compound of claim 9 wherein R2 is acetyl.
 12. A compound of claim 9wherein R2 is bromoacetyl.